I. Field of the Invention
The present invention provides novel tricyclic-bis-enone derivatives (TBEs), as well as the process for the preparation of such TBEs, for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophiclateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins.
II. Description of Related Art
One of the major needs in clinical oncology is the development of effective and safe new agents for chemoprevention. In particular, there is a need for chemopreventative agents targeted at mechanisms known to be involved in the process of carcinogenesis. In recent years, there has been a resurgence of interest in the study of mechanisms of inflammation that relate to carcinogenesis and in the use of such mechanisms as the basis for development of new chemopreventative agents.
The concept that inflammation and carcinogenesis are related phenomena has been the patient of many studies that have attempted to link these two processes in a mechanistic fashion (Sporn and Roberts, 1986; Ohshima and Bartsch, 1994). The enzymes that mediate the constitutive synthesis of NO and prostaglandins from arginine and arachidonate, respectively, have relatively little significance for either inflammation or carcinogenesis. In contrast, inducible nitric oxide synthase (iNOS) and inducible cycloxygenase (COX-2) both have critical roles in the response of tissues to injury or infectious agents (Moncada et al., 1991; Nathan and Xie, 1994; Siebert and Masferrer, 1994; Tamir and Tannebaum, 1996). These inducible enzymes are essential components of the inflammatory process, the ultimate repair of injury, and carcinogenesis. While physiological activity of iNOS and COX-2 may provide a definite benefit to the organism, aberrant or excessive expression of either iNOS or COX-2 has been implicated in the pathogenesis of many disease processes, particularly in chronic degeneration of the central nervous system, carcinogenesis, septic shock, cardiomyopathy, rheumatoid arthritis, and other autoimmune diseases. Unresolved, smoldering inflammation is now understood to play an important role in the pathology of many diseases, including cardiovascular disease (e.g., atherosclerosis and heart failure), diabetes, renal failure, and respiratory diseases such as chronic obstructive pulmonary disease.
The need for new agents to prevent cancer is readily evident from the continuing high mortality rates for the common forms of epithelial cancer, such as carcinoma of the lung, colon, breast, and prostate. As genetic testing now can identify increasing numbers of people who are at high risk for the development of these cancers, it becomes increasingly important to discover new pharmacologic agents that can be used interventionally to prevent this outcome, well before the occurrence of malignant invasive disease. Therefore, it would be advantageous to provide compounds for use in the chemoprevention of cancer that are low in cost for large scale synthesis, and that are water soluble compounds, thus providing use of administration.
Ongoing efforts for the improvement of anti-inflammatory and antiproliferative activity of oleanolic acid analogues led to the discovery of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) and related compounds (Honda et al., 1997, 1998, 1999, 2000a, 2000b, 2002; Suh et al., 1998; 1999; Place et al., 2003).
It has been shown that TP-190 and 222 are potent inhibitors of NO production in mouse macrophages and RAW cells (Honda et al., 2000, 2002). TP-222 is orally potent against inflammatory bowel disease in SvEv129 Rag2−/− mice caused by oral infection with Helicobacter hepaticus. CDDO and several close analogues have also been shown to be potent inducers of apoptosis in cancer cells, with relatively low toxicity in normal tissue. Thus, in addition to their uses in preventing cancer and treating inflammatory diseases, these agents are useful for treating established cancer.

In connection with these investigations, it was found that tricyclic-bis-enone compounds (TBEs) with similar enone functionalities in rings A and C are also a novel class of inhibitors of nitric oxide (NO) production in mouse macrophages (Favaloro et al., 2002) and RAW cells. In particular, bis-cyano enone (±)-TBE-9 (see Table 1, below) is orally active in a preliminary in vivo inflammation model (Favaloro et al., 2002). In addition, (+)-TBE-9, having the opposite configuration to that of CDDO, shows 10 times higher inhibitory activity than (−)-TBE-9 on NO production in mouse macrophages. To the contrary, (−)-TBE-9 is active against MCF-7 mouse breast cancer cell lines, whilst (+)-TBE-9 is inactive (Honda et al., 2003). Therefore, the syntheses of optically active versions of new TBE for a comparison of the biological potency of both enantiomers is very important.
TABLE 1Inhibitory activity of TBE compounds on NO production in primary mousemacrophages stimulated with interferon-γCompound(racemic)IC50 (nM)TBE-1310TBE-2480TBE-353TBE-475TBE-561CDDO0.5hydrocortisone10TBE-691TBE-71600TBE-861TBE-92.1TBE-1019Oleanolic acid>40,000
Given the promising properties shown by the TBE compounds studied so far, it would be advantageous to provide additional TBE compounds, especially those with improved potency, pharmacokinetics, and water solubility.